|About Us :||Faculty :||Effros|
|Rita B. Effros, Ph.D.
Professor, Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA
Director of UCLA Human Tissue Research Center
Elizabeth & Thomas Plott Endowed Chair in Gerontology
Full Member, UCLA Molecular Biology Institute
Associate Member, Cousins Center for Psychoneuroimmunology, UCLA Neuropsychiatric Institute
Both aging and HIV disease are characterized by the loss of immune control over viral infections and by increased cancer incidence. Our approach to dissecting the complex T cell dysfunction associated with these clinical problems has been to focus on a particular facet of T cell biology known as replicative senescence.
This irreversible state of cell cycle arrest, which occurs after T cells have undergone multiple rounds of antigen-driven proliferation, is associated with various functional and genetic changes, such as loss of expression a the key co-stimulatory molecule, CD28), resistance to apoptosis, telomere shortening, and loss of the ability to upregulate telomerase. We have documented that the proportions of T cells with these same characteristics increase with age and with HIV disease progression. Ongoing studies in the lab are addressing the functional aspects of senescent T cells that may contribute to multiple pathologies of aging and AIDS, such as their effect on anti-viral effector activities, alterations in cytokine profiles, and suppressive influences on other types of immune cells. In addition, based on clinical correlations between chronic T cell activation and bone loss, we are interested in the interaction of senescent T cells with osteoclasts and osteoblasts, the cells responsible for bone homeostasis. Finally, we are attempting to reverse or retard the process of replicative senescence in human T cells using telomerase gene therapy, manipulation of CD28 expression, and chemical/hormonal treatment to enhance telomerase activity.
Dagarag M., Evazyan T., Rao N., Effros, RB (2004) Genetic manipulation of telomerase in HIV-specific CD8+ T cells:enhanced anti-viral functions accompany the increased proliferative potential and telomere length stabilization J. Immunol. (in press) .
Valenzuela H and Effros RB (2002) Divergent telomerase patterns in human CD4 and CD8 T cells follwing repeated encounters with the same antigenic stimulus Clinical Immunology 105: 117-125.
Dagarag , MD ,Ng, H.,Lubong, R, *Effros, RB,*Yang, OO ( co-senior authors) (2003) Differential Impairment of Lytic and Cytokine Functions in Senescent HIV-1-Specific Cytotoxic T Lymphocytes. J. Virology 77: 3077-3083.
Panossian, L, Porter,VR, Valenzuela, HF, Zhu, X, Masterman, DL, Reback,E, Cummings J, and Effros RB. (2003) Telomere shortening in T cells correlates with Alzheimer’s disease status Neurobiol of Aging 24: 77-84.
Pawelec, G., Akbar, A., Caruso, C., Effros R.B., Grubeck-Loebenstein, B., & Wikby, A (2004) Is Immunosenescence infections Trends Immunol 25: 406-410.
Effros RB (2004) Replicative senescence of CD8 T cells: potential effects on cancer immune surveillance and immunotherapy Cancer Immunol Immunother ( in press) .